In the pursuit of a developable form of a solid, orally-administered pharmaceutical compound, a number of specific features are sought. Although an amorphous form of a pharmaceutical compound may be developed, compounds having high crystallinity are generally preferred. Often such highly crystalline compounds are salts. It is greatly desired that such a salt would also possess the following features: good stability, good aqueous solubility (preferably >1 mg/mL), good in vivo oral bioavailability, and capability of being obtained in good yield (preferably >50%). However, whether and in which salt form a pharmaceutical compound can form a crystalline solid are highly unpredictable.
The mechanisms of oxytocin are described in U.S. Pat. No. 6,914,160. In man, oxytocin but not vasopressin plasma concentrations are significantly raised at or around ejaculation. Oxytocin does not induce ejaculation itself; this process is 100% under nervous control via 1-adrenoceptor/sympathetic nerves originating from the lumbar region of the spinal cord. The systemic pulse of oxytocin may have a direct role in the peripheral ejaculatory response. It could serve to modulate the contraction of ducts and glandular lobules throughout the male genital tract, thus influencing the fluid volume of different ejaculate components for example. Oxytocin releases centrally into the brain could influence sexual behavior, subjective appreciation of arousal (orgasm) and latency to subsequent ejaculation. Accordingly, the compounds of the present invention can be useful in treating premature ejaculation.
Pre-term births/labour (between 24 and 37 weeks) causes about 60% of infant mortality/morbidity. The density of uterine oxytocin receptors increases significantly by >100 fold during pregnancy and peaks in labour (pre-term and term). Hormone oxytocin is a potent contractor of the uterus and is used for the induction or augmentation of labour. It is believed that a compound which inhibits the uterine actions of oxytocin e.g. oxytocin antagonists, should be useful for the prevention or control of pre-term labour. Endogenous oxytocin peptide can be used clinically to induce labour in pregnant women, and atosiban, an oxytocin antagonist, is an established acute treatment to delay the onset of pre-term labour. Oxytocin is also known to be associated with other disease conditions. Oxytocin antagonists may be useful to delay labour prior to elective caesarean section or transfer of the patient to a tertiary care centre, treatment of sexual dysfunction (male and female), particularly premature ejaculation, obesity, eating disorders, congestive heart failure, arterial hypertension, liver cirrhosis, nephritic or ocular hypertension, obsessive-compulsive disorder and neuropsychiatric disorders.
International patent application WO 03/053443 describes a class of diketopiperazine derivatives which exhibit a particularly useful level of activity as selective oxytocin antagonists.
International Application No. PCT/EP2005/006760, having an International filing date of Jun. 10, 2005 and published as US Publication No. US2007254888A1 the entire disclosure of which is hereby incorporated by reference, describes a number of highly potent oxytocin inhibitors which are indicated as useful in the treatment of diseases or conditions mediated through the action of oxytocin. Specifically disclosed in that application is (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (Example 3, hereinafter Compound A) and its preparation methods.
Since the discovery of Compound A, significant efforts have been put into identifying crystalline salt forms that are more suitable for pharmaceutical development; however, many acid addition salts do not form crystalline salt. The present inventors have now discovered two novel crystalline forms of (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione benzenesulfonate salt, hereinafter Compound A-Form 1 and Compound A-Form 2.